scholarly journals Suppression of experimental autoimmune encephalomyelitis using estrogen receptor-selective ligands

2005 ◽  
Vol 185 (2) ◽  
pp. 243-252 ◽  
Author(s):  
M Merle Elloso ◽  
Kristen Phiel ◽  
Ruth A Henderson ◽  
Heather A Harris ◽  
Steven J Adelman
Keyword(s):  
Multiple Sclerosis ◽  
Estrogen Receptor ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Immune Responses ◽  
Clinical Symptoms ◽  
Protective Effects ◽  
Autoimmune Encephalomyelitis ◽  
Selective Agonist ◽  
Selective Ligands ◽  
Experimental Autoimmune

Estrogens have been shown to modulate disease activity in experimental autoimmune encephalomyelitis (EAE), the mouse model for multiple sclerosis. Consistent with these findings, the severity of disease is reduced in pregnant women with multiple sclerosis when levels of estrogens are high. Estrogens bind to two known estrogen receptors (ER), ERα and ERβ. The relative contribution of these receptors to estrogen-mediated suppression of EAE was explored using ER-selective ligands. The ER antagonist ICI 182 780 reversed the suppressive effects of 17β-estradiol (E2), demonstrating that the protective effects of E2 on disease are dependent upon ER signaling. Treatment of SJL mice with the ERα-selective agonist proteolipid protein (PPT) prior to the induction of disease resulted in suppression of clinical symptoms of disease, whereas treatment with an ERβ-selective agonist (WAY-202041) had no effect. Treatment of mice with PLP peptide 139–151 (PPT) was also associated with decreased immune responses associated with disease. Consistent with its lack of effect on disease, the ERβ agonist had minimal effects on immune responses. The use of selective estrogen receptor modulators (SERMs) in this model was also explored, and we show that raloxifene and WAY-138923 were also effective in suppressing disease. These results demonstrate the beneficial effects of estrogen receptor ligands, in particular ERα-selective ligands, and may have implications in the development of therapeutic strategies for multiple sclerosis.

scholarly journals Antiinflammatory Properties of a Plant-Derived Nonsteroidal, Dissociated Glucocorticoid Receptor Modulator in Experimental Autoimmune Encephalomyelitis

2009 ◽  
Vol 94 (12) ◽  
pp. 5184-5184
Author(s):  
Geert van Loo ◽  
Mozes Sze ◽  
Nadia Bougarne ◽  
Jelle Praet ◽  
Conor McGuire ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Glucocorticoid Receptor ◽  
Clinical Symptoms ◽  
Neuronal Damage ◽  
Nuclear Factor Κb ◽  
Myelin Oligodendrocyte Glycoprotein ◽  
Nuclear Factor ◽  
Autoimmune Encephalomyelitis ◽  
Experimental Autoimmune

Abstract Compound A (CpdA), a plant-derived phenyl aziridine precursor, was recently characterized as a fully dissociated nonsteroidal antiinflammatory agent, acting via activation of the glucocorticoid receptor, thereby down-modulating nuclear factor-κB-mediated transactivation, but not supporting glucocorticoid response element-driven gene expression. The present study demonstrates the effectiveness of CpdA in inhibiting the disease progress in experimental autoimmune encephalomyelitis (EAE), a well-characterized animal model of multiple sclerosis. CpdA treatment of mice, both early and at the peak of the disease, markedly suppressed the clinical symptoms of EAE induced by myelin oligodendrocyte glycoprotein peptide immunization. Attenuation of the clinical symptoms of EAE by CpdA was accompanied by reduced leukocyte infiltration in the spinal cord, reduced expression of inflammatory cytokines and chemokines, and reduced neuronal damage and demyelination. In vivo CpdA therapy suppressed the encephalogenicity of myelin oligodendrocyte glycoprotein peptide-specific T cells. Moreover, CpdA was able to inhibit TNF- and lipopolysaccharide-induced nuclear factor-κB activation in primary microglial cells in vitro, in a differential mechanistic manner as compared with dexamethasone. Finally, in EAE mice the therapeutic effect of CpdA, in contrast to that of dexamethasone, occurred in the absence of hyperinsulinemia and in the absence of a suppressive effect on the hypothalamic-pituitary-adrenal axis. Based on these results, we propose CpdA as a compound with promising antiinflammatory characteristics useful for therapeutic intervention in multiple sclerosis and other neuroinflammatory diseases.

scholarly journals Antiinflammatory Properties of a Plant-Derived Nonsteroidal, Dissociated Glucocorticoid Receptor Modulator in Experimental Autoimmune Encephalomyelitis

2009 ◽  
Vol 30 (7) ◽  
pp. 931-931
Author(s):  
Geert van Loo ◽  
Mozes Sze ◽  
Nadia Bougarne ◽  
Jelle Praet ◽  
Conor McGuire ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Glucocorticoid Receptor ◽  
Clinical Symptoms ◽  
Neuronal Damage ◽  
Nuclear Factor Κb ◽  
Myelin Oligodendrocyte Glycoprotein ◽  
Nuclear Factor ◽  
Autoimmune Encephalomyelitis ◽  
Experimental Autoimmune

Abstract Compound A (CpdA), a plant-derived phenyl aziridine precursor, was recently characterized as a fully dissociated nonsteroidal antiinflammatory agent, acting via activation of the glucocorticoid receptor, thereby down-modulating nuclear factor-κB-mediated transactivation, but not supporting glucocorticoid response element-driven gene expression. The present study demonstrates the effectiveness of CpdA in inhibiting the disease progress in experimental autoimmune encephalomyelitis (EAE), a well-characterized animal model of multiple sclerosis. CpdA treatment of mice, both early and at the peak of the disease, markedly suppressed the clinical symptoms of EAE induced by myelin oligodendrocyte glycoprotein peptide immunization. Attenuation of the clinical symptoms of EAE by CpdA was accompanied by reduced leukocyte infiltration in the spinal cord, reduced expression of inflammatory cytokines and chemokines, and reduced neuronal damage and demyelination. In vivo CpdA therapy suppressed the encephalogenicity of myelin oligodendrocyte glycoprotein peptide-specific T cells. Moreover, CpdA was able to inhibit TNF- and lipopolysaccharide-induced nuclear factor-κB activation in primary microglial cells in vitro, in a differential mechanistic manner as compared with dexamethasone. Finally, in EAE mice the therapeutic effect of CpdA, in contrast to that of dexamethasone, occurred in the absence of hyperinsulinemia and in the absence of a suppressive effect on the hypothalamic-pituitary-adrenal axis. Based on these results, we propose CpdA as a compound with promising antiinflammatory characteristics useful for therapeutic intervention in multiple sclerosis and other neuroinflammatory diseases.

Protective Effects on Central Nervous System by Acidic Polysaccharide of Panax ginseng in Relapse-Remitting Experimental Autoimmune Encephalomyelitis-Induced SJL/J Mice

2016 ◽  
Vol 44 (06) ◽  
pp. 1099-1110 ◽  
Author(s):  
So Jin Bing ◽  
Danbee Ha ◽  
Insun Hwang ◽  
Eunjin Park ◽  
Ginnae Ahn ◽  
...  
Keyword(s):  
T Cells ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Panax Ginseng ◽  
Clinical Symptoms ◽  
Inflammatory Factors ◽  
Protective Effects ◽  
Autoimmune Encephalomyelitis ◽  
Acidic Polysaccharide ◽  
Relapsing Remitting ◽  
Experimental Autoimmune

Bearing pathologic and clinical similarities to human multiple sclerosis (MS), experimental autoimmune encephalomyelitis (EAE) is used as a murine model to test potential therapeutic agents for MS. Recently, we reported the protective effects of an acidic polysaccharide of Panax ginseng (APG) in C57BL/6 strain-dependent EAE, a model of primary progressive MS. In this study, we extend our previous findings on the therapeutic capacity of APG in relapsing-remitting EAE (rr-EAE), the animal model to closely mimic recurrent inflammatory demyelination lesions of relapsing-remitting MS. Treatments with APG led to a significant reduction of clinical symptoms and the relapse rate of EAE than vehicle treatments. Consistent with this, histological examination revealed that APG markedly modulated the infiltration of CD4[Formula: see text] T cells and CD11b[Formula: see text] macrophages into the spinal cord and the APG-treated CNS was devoid of demyelination and axonal damages. In addition, APG decreased the proliferation of peripheral PLP-reactive T cells and the production of pro-inflammatory factors such as IFN-[Formula: see text], IL-17 and TNF-[Formula: see text]. The fact that APG can induce clinically beneficial effects to distinct types of EAE furthers our understanding on the basis of its immunosuppression in EAE and, possibly, in MS. Our results suggest that APG may serve as a new therapeutic agent for MS as well as other human autoimmune diseases, and warrants continued evaluation for its translation into therapeutic application.

scholarly journals Localisation of clozapine during experimental autoimmune encephalomyelitis and its impact on dopamine and its receptors

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Katharina Robichon ◽  
Sven Sondhauss ◽  
T. William Jordan ◽  
Robert A. Keyzers ◽  
Bronwen Connor ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Mass Spectrometry ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Dopamine Receptors ◽  
Dopamine Receptor ◽  
Brain Regions ◽  
Receptor Expression ◽  
Protective Effects ◽  
Autoimmune Encephalomyelitis ◽  
Experimental Autoimmune

AbstractMultiple sclerosis is a disease characterised by axonal demyelination in the central nervous system (CNS). The atypical antipsychotic drug clozapine attenuates experimental autoimmune encephalomyelitis (EAE), a mouse model used to study multiple sclerosis, but the precise mechanism is unknown and could include both peripheral and CNS–mediated effects. To better understand where clozapine exerts its protective effects, we investigated the tissue distribution and localisation of clozapine using matrix-assisted laser desorption ionization imaging mass spectrometry and liquid chromatography-mass spectrometry. We found that clozapine was detectable in the brain and enriched in specific brain regions (cortex, thalamus and olfactory bulb), but the distribution was not altered by EAE. Furthermore, although not altered in other organs, clozapine levels were significantly elevated in serum during EAE. Because clozapine antagonises dopamine receptors, we analysed dopamine levels in serum and brain as well as dopamine receptor expression on brain-resident and infiltrating immune cells. While neither clozapine nor EAE significantly affected dopamine levels, we observed a significant downregulation of dopamine receptors 1 and 5 and up-regulation of dopamine receptor 2 on microglia and CD4+-infiltrating T cells during EAE. Together these findings provide insight into how neuroinflammation, as modelled by EAE, alters the distribution and downstream effects of clozapine.

scholarly journals Therapeutic effect of nucleoside analogs on experimental autoimmune encephalomyelitis in dark agouti rats

2006 ◽  
Vol 58 (1) ◽  
pp. 13-20 ◽  
Author(s):  
Danijela Stojkov ◽  
Irena Lavrnja ◽  
Sanja Subasic ◽  
Ivana Bjelobaba ◽  
Sanja Pekovic ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Animal Model ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Clinical Symptoms ◽  
Combined Treatment ◽  
Nucleoside Analogs ◽  
Dark Agouti ◽  
Autoimmune Encephalomyelitis ◽  
Additive Action ◽  
Experimental Autoimmune

Experimental autoimmune encephalomyelitis (EAE) is a commonly used animal model of the human neurological disorder multiple sclerosis. The purpose of the present study was to investigate the effect of combined treatment with two nucleoside analogs, ribavirin and tiazofurin, on development of EAE actively induced in highly susceptible dark agouti rats. The obtained results showed that ribavirin and tiazofurin applied either separately or in combination from the onset of the firstsymptoms of EAE after its induction (therapeutic treatment) significantly suppressed EAE?s clinical symptoms. However, the most pronounced effect was gained with combined treatment, probably as a result of synergistic/additive action.

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